Animals must relentlessly explore their surroundings in search of food, water, and shelter, in order to survive. Animals with complex nervous systems utilize multiple sensory modalities such as vision, touch, and hearing to perceive spatial patterns that reflect the physical structure of their environment. But can animals with much simpler nervous systems detect and discriminate spatial patterns in their environment as well? To address this question, we investigated the roundworm C. elegans, which feeds and reproduces in decomposing fruits and plant stems (Barrière and Félix, 2014). C. elegans has only 302 neurons and lack vision and hearing, mainly relying on smell and touch to sense their environment. C. elegans uses the sense of touch (or mechanosensation) to detect physical contact with external objects. For example, touch to the worm body or nose elicits reflex withdrawal responses (Chalfie and Sulston, 1981, Chalfie and Wolinsky, 1990; Kaplan and Horvitz, 1993; Sulston et al., 1975; Way and Chalfie, 1989), which allows the worms to quickly avoid potential danger. Beyond reflex, mechanosensation could also provide important information about the physical structure of the environment, aiding in navigation and spatial orientation. Indeed, mechanosensory detection of food elicits a slowing in C. elegans locomotion, increasing the time spent where food is present (Sawin et al., 2000). However, it remains unknown whether C. elegans mechanosensation is limited to such binary distinctions between the presence and absence of food, or whether it enables more general and refined perception of particular spatial patterns, and if so, how this depends on context and experience. These questions are important for determining to what extent a simple animal can sense the spatial arrangement of physical features in its surroundings, providing general insights about how animals perceive spatial patterns.

Here, we report that C. elegans has the ability to discriminate spatial patterns using mechanosensory-dependent dopamine signaling. This spatial pattern selectivity is not a fixed behavior. Instead, it is modified by experience and by internal states such as starvation. Among C. elegans wild isolates, the absolute degree of spatial pattern preference is tuned by natural variations in the mechanosensory channel TRP-4 and the dopamine receptor DOP-3, leading to differential behavioral responses to identical environmental settings. These results suggest that the sense of the physical surroundings may undergo rapid evolutionary expansion to diversify the choice of preferred habitat, and perhaps to benefit the survival of the species.

To study how spatial patterns in its surroundings may impact worm behavior, we examined worm locomotion in microfluidic chambers comprising four patterns of PDMS (polydimethylsiloxane) pillars, designated quad-chambers (Figure 1A and Figure 1—figure supplement 1A). Pillar density increased in the four patterns from zero pillars (Pattern I) to the highest density of pillars (Pattern IV). We found that the Bristol N2 strain exhibits a strong preference for pattern IV (Figure 1B). Approximately 63% of N2 worms were found in the section containing pattern IV 60 min after entering the chamber. By contrast, we observed only 9–15% of worms in each of the other sections I, II and III (Figure 1C) with lower pillar densities. The strong preference for pattern IV was also indicated by a high positive value of a spatial pattern preference index (Figure 1C; Methods). To investigate the robustness of this pattern selectivity, we quantified N2 preference for pattern IV at various time points (Figure 1—figure supplement 1B). Pattern IV preference was very stable between 60 and 90 min, but was reduced at 120 min. This decrease was likely due to starvation, as addition of food (OP50 bacteria) into the chamber prolonged the preference for pattern IV, which lasted at least 180 min (Figure 1—figure supplement 1C). Consistent with this notion, worms that had already been starved prior to the experiment exhibited a significant reduction in pattern IV preference (Figure 1—figure supplement 1D), indicating that feeding state (starvation) can override an inherent preference for pattern selectivity.

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To test whether pattern selectivity is based on individual choice or group behavior, we performed cumulative single-worm analyses. Single-worm pattern preference index values were similar to those obtained in population experiments (Figure 1—figure supplement 2A), indicating that pattern selectivity is an individual rather than group behavior. To identify the sensory modality used for pattern selection, we analyzed mutant worms that have defects in either oxygen or touch sensation. C. elegans exhibits aggregation behavior at optimal oxygen levels (Cheung et al., 2004; Gray et al., 2004). We thus examined whether oxygen sensation might play a role in the observed clustering within pattern IV. To this end, we tested mutant worms that lack the GCY-35 soluble guanylate cyclase and are defective in oxygen-dependent aggregation, bordering, and social feeding behaviors (Cheung et al., 2004; Gray et al., 2004). However, these mutant gcy-35 worms continued to show preference for pattern IV (Figure 1D), indicating that pattern IV selectivity was independent of possible variations in oxygen levels and oxygen sensing. By contrast, mutant worms with dysfunctional MEC-10 DEG/ENaC channels showed a significant reduction in their preference for pattern IV (Figure 1E). To understand where MEC-10 functions, we performed cell-specific rescue experiments. As expected, single-copy Pmec-10::mec-10 transgenes that drive MEC-10 expression in the six touch receptor neurons and in PVD and FLP neurons fully restored the preference for pattern IV. Expression of MEC-10 under Pegl-44 in FLP and HSN neurons (Wu et al., 2001) also rescued the defects in mec-10(tm1552) mutant worms. By contrast, MEC-10 expression in the six touch receptor neurons (driven by Pmec-18) did not recover the preference for pattern IV. Together, these data indicate that MEC-10 acts in the polymodal nociceptive FLP neurons to support the selection of pattern IV.

To determine whether pattern selectivity depends on the particular absolute pillar density of pattern IV, we used a chamber consisting of patterns I and III only (Figure 1—figure supplement 2D). In this chamber, N2 worms showed a clear preference for pattern III (Figure 1—figure supplement 2E), even though this is a non-favored pattern in the quad-chamber. We therefore conclude that pattern selectivity is based on comparison between different spatial patterns i.e., environmental context, rather than on the specific structural arrangement of pattern IV.

We next investigated the strategies that worms use to select pattern IV in the quad-chamber. First, we considered local effects occurring at the boundaries between adjacent patterns. We tracked worms that left pattern IV and entered into the less desired pattern III (Figure 2A), and found that these worms re-crossed back into the preferred pattern IV at a much higher rate than worms already within pattern IV (Figure 2B). We also found an increase in both reversal and turning rates when worms cross the IV-to-III boundary (Figure 2C). Therefore, worms sense local changes in pattern density, and respond quickly to unfavorable changes by reorientation, reinforcing our finding of their ability to make decisions based on comparisons of spatial density. Second, we examined whether worm locomotion within pattern IV was affected by the presence of neighboring patterns. We hypothesized that preceding experience of alternative spatial configurations would have a lasting impact on worm behavior within preferred pattern IV. To test this hypothesis, we designed an additional chamber (designated uni-chamber; Figure 2D) containing only a pattern IV pillar configuration throughout its surface and no other patterns. We compared the speed and pause rates of worms within pattern IV in both quad- and uni- chambers. We found that worms in pattern IV of the quad-chamber moved more slowly and paused more than worms in the uni-chamber (Figure 2E–F). Such slowing and pausing could prolong the stay of worms in pattern IV. Together, these data suggest that the clustering of worms in pattern IV is due to both real-time responses to pattern changes upon boundary crossing and to longer-lasting effects caused by the experience of other less desired patterns. Thus, without vision or hearing, C. elegans can take advantage of mechanosensory information to compare and select between spatial patterns in its environment.

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We next set to explore the molecular basis for the observed spatial pattern selectivity. Several features of this behavior prompted us to investigate the contribution of dopamine signaling. In C. elegans, dopamine regulates a variety of behaviors including locomotion, mechanosensation, food availability, touch habituation, and the swim-to-crawl transition (Calhoun et al., 2015; Chase et al., 2004; Hills et al., 2004; Kindt et al., 2007; Sanyal et al., 2004; Sawin et al., 2000; Vidal-Gadea et al., 2011). In particular, dopamine signals decrease locomotion rates when worms enter a food source (a lawn of bacteria) (Sawin et al., 2000), and increase returning frequency when worms leave the bacteria lawn (Hills et al., 2004). To test whether dopamine is required also for spatial pattern selectivity, we examined cat-2(e1112) animals, which lack the CAT-2 tyrosine hydroxylase and are defective in dopamine biosynthesis (Lints and Emmons, 1999). We observed that cat-2 mutant animals have disrupted pattern selectivity, as they showed reduced preference for pattern IV in the quad-chambers (Figure 3A). Addition of exogenous dopamine restored the accumulation of cat-2 mutants within pattern IV (Figure 3A), demonstrating that the defect in spatial pattern selectivity of cat-2 mutants is due to the lack of dopamine. To determine the dopamine receptor responsible for the selectivity, we analyzed mutant worms with impaired dopamine receptors. We found that disrupting the D2-like receptor DOP-3, but not other dopamine receptors (DOP-1, DOP-2, and DOP-4), led to a reduced preference for pattern IV (Figure 3B). DOP-3 is expressed in a variety of neurons in the head, ventral cord and tail (Chase et al., 2004). The site-of-action of DOP-3 for pattern selection is unknown.

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To identify the molecular sensor that links mechanosensation, dopamine, and spatial pattern preference, we studied mutant worms that lack TRP-4, a stretch receptor expressed in the CEP, ADE, and PDE dopaminergic neurons and the DVA and DVC interneurons (Hu et al., 2011; Kang et al., 2010; Li et al., 2006). TRP-4 is the pore-forming subunit of mechanotransduction channels (Kang et al., 2010; Li et al., 2006). Mutant trp-4(ok1605) worms significantly reduced their preference for pattern IV (Figure 3C) and did not show the enhanced returning behavior after crossing the boundary between section IV and III (Figure 3D). To confirm that the defects in pattern selection are due to the lack of TRP-4 function, we generated a second allele trp-4(pek220) using CRISPR/CAS9 and homologous recombination (Figure 3—figure supplement 1). We found that trp-4(pek220) mutant worms exhibit similar defects as trp-4(ok1605) worms, confirming that the pattern IV preference requires TRP-4. The defects of trp-4 single mutants were similar to trp-4; cat-2 and trp-4; dop-3 double mutants, indicating that trp-4 acts in the same dopamine pathway as cat-2 and dop-3 (Figure 3E). Single-copy transgenes that express TRP-4 in dopaminergic neurons restored the preference for pattern IV (Figure 3C), further demonstrating a role of TRP-4 in dopaminergic neurons in mediating spatial pattern selectivity. Together, these data elucidate a signaling mechanism for the stretch receptor TRP-4, dopamine, and the dopamine receptor DOP-3, coupling spatial pattern detection with the behavioral preference of animals.

Recent studies have shown that natural genetic variations influence how C. elegans interacts with environmental cues such as food, oxygen, microbial pathogens, and neighboring worms (Bendesky and Bargmann, 2011; Bendesky et al., 2012, 2011; Chang et al., 2011; Persson et al., 2009). The physical structure of the environment is another important feature that varies with habitat. We therefore hypothesized that C. elegans strains from different natural habitats might differ in their selectivity of spatial patterns. We thus examined a wild isolate of C. elegans, Hawaiian CB4856 (designated HW) in the spatial pattern preference assay. Interestingly, we found that unlike N2, HW worms failed to aggregate in pattern IV of the quad-chambers (Figure 4A, B), and their returning behavior at boundaries was significantly reduced in comparison to N2 worms (Figure 4C). In addition, HW worms exhibited similar traveling speed and pause rates in uni- and quad-chambers (Figure 4—figure supplement 1), indicating that mechanosensory experience had little impact on HW behavior. Several studies have shown that behavioral differences between N2 and HW could be explained by laboratory-derived genetic changes (e.g., allelic variations in npr-1 and glb-5; reviewed in Sterken et al. (2015). To test whether this is the case for spatial pattern selectivity, we examined the LSJ1 strain, a sibling of N2 that was cultivated separately after isolation. We found that the LSJ1 strain showed similar behavior to N2 worms in the spatial pattern preference assay (Figure 4B), suggesting that the difference in spatial pattern selectivity is not due to domestication-derived alleles.

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Interestingly, the stretch receptor TRP-4 in the HW strain carries three amino acid substitutions (M36I, G41S, and E67G; Figure 5A) (Thompson et al., 2013). The trp-4 gene is located on chromosome I in C. elegans. An N2/HW hybrid strain that carries the HW Chromosome I in an N2 background behaved like the HW strain in the spatial pattern preference assay. However, hybrid strains that carry other HW chromosomes in the N2 background were indistinguishable from N2 worms (Figure 5B), with the exception of those with HW Chromosome X, which showed a minor but significant reduction in the preference for pattern IV. These data are consistent with a role of trp-4 in determining the natural variation in spatial pattern selectivity. They also suggest that other gene(s) on Chromosome X may contribute to the polymorphic behavior. Next, we isolated recombinant inbred lines (RIL) from a cross between N2 and N2/HW hybrids that carry the HW Chromosome I. As shown in Figure 5C, two RIL strains behaved differently in the spatial pattern preference assay; one that carries the N2 trp-4 gene showed preference for pattern IV, but another one with HW trp-4 did not. To confirm the role of TRP-4 in spatial preference polymorphism, we performed rescue experiments using single-copy transgenes expressing either N2 or HW trp-4 cDNA in dopaminergic neurons. N2 trp-4 cDNA fully restored the selectivity defects of the trp-4(ok1605) mutant worms. By contrast, HW trp-4 cDNA showed only low levels of rescue (Figure 5D). These data confirm that N2 TRP-4 is required for the spatial pattern preference observed in the Bristol strains. To test whether N2 TRP-4 is sufficient for endowing the HW strains with spatial pattern selectivity, we overexpressed N2 TRP-4 in HW worms. Because TRP channels are expected to form tetramers, we reasoned that overexpression of N2 TRP-4 might replace the HW TRP-4 channels. Indeed, we found that N2 TRP-4 but not HW TRP-4 overexpression caused HW worms to show spatial pattern selectivity similar to that of N2 (Figure 5E).

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The substitution of three residues in HW TRP-4 occurs at the N-terminal region that is adjacent to Ankyrin repeats (Figure 5A). In flies, the Ankyrin repeats of NOMPC (the TRP-4 homologue) directly bind microtubules, and they are essential for mechanogating of the NOMPC channels (Zhang et al., 2015). To understand whether the three residue substitutions alter TRP-4 properties, we recorded electrophysiological responses of the dopaminergic CEP neurons to small mechanical displacements (Figure 6A) (Kang et al., 2010). The mechanoreceptor current in CEP neurons is mediated by TRP-4, and the amplitude of the current depends on the strength of the applied mechanical force. In agreement with a previous study (Kang et al., 2010), a displacement of 0.5 μm was sufficient to elicit TRP-4 mediated current in N2 worms, and the current was saturated at 3 μm displacement (Figure 6B). Interestingly, the sensitivity of HW TRP-4 to mechanical stimuli was significantly reduced. Larger mechanical displacement was required to generate currents with similar amplitudes (Figure 6A–B). These results are consistent with the findings that the N-terminal region of the TRP-4 homologue NOMPC is required for mechanogating in flies (Zhang et al., 2015). It is worth noting that, when mechanical stimuli are sufficiently strong, the HW TRP-4 is fully active (Figure 6C). Consistently, we found that an even higher density of pillars (novel pattern V) enhanced the enrichment of HW worms, but not of trp-4(ok1605) mutants (Figure 6D). Together, these findings indicate that amino acid substitutions in HW TRP-4 reduce the sensitivity to mechanical stimuli, which could subsequently alter spatial pattern perception in HW worms. Interestingly, whereas a single-copy HW TRP-4 transgene failed to restore spatial preference (Figure 5E), it completely rescued swimming/crawling transition in the trp-4(ok1605) mutant worms (Figure 5—figure supplement 1), suggesting that various types of TRP-4 dependent behaviors are tuned to different levels of mechanogating sensitivity.

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Finally, we analyzed spatial pattern selectivity of ten additional wild isolates, for which complete genome sequences are available (Thompson et al., 2013). We found that five wild isolates exhibited a spatial preference like N2. Two isolates (AB1 and JU397) with substituted residues in TRP-4 exhibited defects in preference for pattern IV in the quad-chambers (Figure 7A). The TRP-4 channels in AB1 and JU397 each carry two substitutions (G41S and E67G), suggesting that the third substitution M36I in the HW strain is not required. A third isolate (CB4854) also carries two substitutions (E67G and I152M) in TRP-4; however, these worms did not show significant defects in the spatial pattern preference assay (Figure 7A). The most parsimonious explanation is that the G41S substitution is the key residue that modulates TRP-4 mechanosensitivity. However, it is also possible that E67G is important, but the combination of E67G and I152M suppresses the impact of E67G.

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Intriguingly, three wild isolates (CB4853, JU300, and JU322) showed altered spatial pattern selectivity despite having N2-like TRP-4 sequence (Figure 7A). Closer examination of their genome sequences revealed that all three strains carry a substituted residue in DOP-3 at the same position (A273G). Upon editing the dop-3 gene in N2 worms using CRISPR/Cas9 (Friedland et al., 2013), we found that the edited worms with the A273G substitution lost their spatial pattern selectivity (Figure 7B). These experiments indicate that the DOP-3 A273G mutation is sufficient to impair spatial pattern preference even with fully functional TRP-4. Therefore, the diversity of spatial pattern selectivity may arise from variations in either the detector that senses changes in the external world (e.g., TRP-4), or the neuromodulator signals that define the internal state of animals (e.g., dopamine and its receptors).

These results demonstrate that C. elegans is able to utilize touch sensation to discern different spatial patterns in the environment. Previous studies have shown that nematodes can evaluate their environment by sensing food (Calhoun et al., 2015) and chemicals (Albrecht and Bargmann, 2011). Our findings add a new dimension to the ‘mind’ of the worm by demonstrating a capability to perceive physical patterns in the environment. In many animal species, touch perception plays a key role in guiding exploration of the physical world. For example, insects carry antennae to collect tactile information during locomotion, rodents use whiskers to detect spatial settings, and sea mammals use facial hairs to trace changes in water flow patterns caused by swimming fish. Using a substantially simpler nervous system, C. elegans is able to detect spatial patterns, and to use mechanosensory information about the overall environment to form spatial pattern preferences. While primitive, this sense of physical space in worms is highly dynamic – it is tightly regulated by experience (Figure 2E,F), spatial context (Figure 1—figure supplement 2D,E), and food availability (Figure 1—figure supplement 1C,D). Together, our findings elucidate a basic but surprising sense of physical patterns in the surrounding environment in a simple nervous system of 302 neurons.

The selectivity of spatial patterns in C. elegans requires dopamine, which may serve as a ‘reward’ signal that connects the sensation of spatial patterns with innate preferences (Schultz et al., 1997). In higher animals, the existence of sensory modalities such as vision and hearing and associated brain structures, substantially expand the richness and quality of available information about the physical structure of their environment. Nevertheless, together with previous findings implicating dopamine in spatial attention (Bellgrove et al., 2007) and spatial memory (Murphy et al., 1996), as well as in disorders such as agoraphobia in humans (Perna et al., 2011), our study suggests that the coupling between dopamine signaling and a sense of spatial features is an ancestral feature of animal nervous systems.

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Author details

1. Bicheng Han

   Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States

   Present address

   Department of Organismic and Evolutionary Biology, Center for Brain Science, Harvard University, Cambridge, United States

   Contribution

   BH, Conceptualization, Data curation, Formal analysis, Investigation, Writing—original draft, Designed and carried out experiments, collected the data and assisted with preparing the manuscript

   Competing interests

   The authors declare that no competing interests exist.

2. Yongming Dong

   Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States

   Contribution

   YD, Data curation, Validation, Investigation, Designed and carried out electrophysiology experiments, Collected and analyzed the data

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-6510-0913

3. Lin Zhang

   Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States

   Contribution

   LZ, Validation, Methodology, Designed and generated transgenic C. elegans strains, Assisted with behavioral testing and validation

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-9065-4168

4. Yan Liu

   Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States

   Contribution

   YL, Assisted with behavioral testing, data collection, data analysis, and validation

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-5631-7272

5. Ithai Rabinowitch

   Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States

   Contribution

   IR, Writing—original draft, Writing—review and editing, Assisted with preparing and revising the manuscript

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0003-0361-9055

6. Jihong Bai

   Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States

   Contribution

   JB, Conceptualization, Supervision, Funding acquisition, Investigation, Methodology, Writing—original draft, Writing—review and editing, Prepare and revise the manuscript, designed all experiments, and supervised the project

   For correspondence

   jbai@fredhutch.org

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0001-6773-2175

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